Three recent commentaries and a summary of the 2011 NCI Expert Panel Workshop on Early-life Events and Cancer have emphasized the urgent need for more epidemiological research on early life exposures and adult cancers. Puberty is associated with a physiological decrease in insulin sensitivity and during the growth period concentrations of growth factors such as insulin-like growth factor 1 (IGF1) are up to four times higher than during adulthood. Thus, childhood and adolescence may represent periods with higher susceptibility to risk factors associated with hyperinsulinemia, increased IGF1 levels or increased DNA damage and inefficient DNA repair. The vast majority of studies on risk factors and colorectal cancer (CRC) have focused on exposures in mid- to late life and very little is known about timing of exposure, i.e. at which stage(s) during the life cycle a given exposure is etiologically relevant; or the effect of cumulative exposure. We previously found that in the Nurses' Health Study II (NHS II), independent of adult exposures, higher body fatness during childhood and a western dietary pattern during adolescence was associated with higher risk of colorectal adenoma. We propose to utilize the unique data resources of the NHS II and examine the association between early life risk factors and risk of adenoma and CRC. The NHS II was started in 1989 when over 116,000 female nurses provided information on lifestyle and medical history. Starting in 1991, we also collected information on diet. Information on lifestyle was updated every two years and diet and activity every four years. In 1997, we collected data on lifetime physical activity and in 1998 about 45,000 women completed a 124-item semi-quantitative food frequency questionnaire on their diet during high school. Aim 1 will assess the association between amount, intensity of physical activity and sedentary behavior during childhood and adolescence and risk of colorectal neoplasia. Aims 2 and 3 will focus on two dietary factors (milk and folate) hypothesized to exert differential effects on carcinogenesis depending on the timing of exposure. Crucial components of this proposal include: a) availability of both early life and adult exposures, allowing us to examine independent and joint associations, which will help to improve cancer prevention strategies, e.g., whether a higher risk conferred by diet and lifestyle during childhood or adolescence can be mitigated by modifications to diet and lifestyle during adulthood; and b) assessment of CRC and its intermediate adenoma as outcome, which will also help to better understand pathways underlying the transformation from adenoma to carcinoma. Thus, our proposal will provide more insight into the etiology of CRC and inform cancer prevention strategies, e.g., whether to shift the focus of some interventions in mid- to late adulthood to interventions that start in earlier stages of the life course and whether to use information on risk factors throughout the life course to guide prevention counseling.